Current evidence demonstrates that patients who suffer from long-term SARS-CoV-2 symptoms [i.e., post-COVID-19 syndrome (PCS)] often present muscle fatigue and dyspnea. This is discussed to be a result of vascular dysfunction and oxidative stress triggered by the infection. However, its effects on the microvasculature remain unknown. Sixty-two participants (61.3% women) were recruited [50.0 ± 11.8 yr, body mass index (BMI) 27.6 ± 5.3 kg·m-2, maximal oxygen uptake (V̇o2max) 26.2 ± 9.4 mL·kg-1·min-1] from the epidemiology and clinical characteristics of PCS (EPILOC) phase 2 study. Participants were divided into either a case group (patients with new or prolonged symptoms and impaired general health or work ability compatible with persistent PCS) or a control group (symptom-free age-sex-matched patients with uneventful recovery after COVID-19). The brachial-ankle pulse wave velocity (baPWV) was assessed via the BOSO-ABI system 100. To evaluate the microvascular function, a tissue oxygen saturation reperfusion rate assessment using near-infrared spectroscopy was performed on the flexor digitorum superficialis muscle. No significant statistical differences were observed between the case and control groups in age, BMI, and baPWV (P textgreater 0.05). The control group achieved a greater V̇o2max than the case group (P = 0.02). After adjusting for V̇o2max, a significant effect of group [F(1,52) = 5.28, P = 0.026] in microvascular function was observed, with the case group presenting lower values than the control group (β = -0.53, P = 0.02). No a priori power calculation was performed-post hoc sensitivity analysis indicated a minimum detectable effect of Cohen’s d = 0.72, and secondary outcomes should be interpreted cautiously. Our results indicate a reduced microvascular function in patients with PCS, as compared with the control group. Such impairment may be linked to the prolonged symptoms experienced by patients, causing capillary flow disturbances and, subsequently, limiting muscle oxygen uptake.NEW & NOTEWORTHY We provide objective evidence that skeletal muscle microvascular reactivity is significantly impaired in patients with post-COVID-19 syndrome (PCS) compared with recovered controls. Using near-infrared spectroscopy, we demonstrate that this blunted microvascular reperfusion persists even after adjusting for maximal oxygen uptake (V̇o2max). These findings suggest that microvascular dysfunction is a distinct pathophysiological feature of PCS that may contribute to exercise intolerance and fatigue, independent of physical deconditioning.